As reviewed in Susan Elmore, Toxicol Pathol. 2007; 35(4): 495-516, apoptosis occurs normally during development and aging and as a homeostatic mechanism to maintain cell populations in tissues. Apoptosis also occurs as a defense mechanism such as in immune reactions or when cells are damaged by disease or noxious agents (Norbury and Hickson, 2001). Although there is a wide variety of stimuli and conditions, both physiological and pathological, that can trigger apoptosis, not all cells will necessarily die in response to the same stimulus. Irradiation or drugs used for cancer chemotherapy results in DNA damage in some cells, which can lead to apoptotic death through a p53-dependent pathway. Some hormones, such as corticosteroids, may lead to apoptotic death in some cells (e.g., thymocytes) although other cells are unaffected or even stimulated. Some cells express Fas or TNF receptors that can lead to apoptosis via ligand binding and protein cross-linking. Other cells have a default death pathway that must be blocked by a survival factor such as a hormone or growth factor. There is also the issue of distinguishing apoptosis from necrosis, two completely different processes that can occur independently, sequentially, as well as simultaneously (Hirsch, 1997; Zeiss, 2003). Generally, necrosis is the result of acute injury to the cell, whereas apoptosis is controlled by a diverse group if signals that can be either intrinsic (intracellular) or extrinsic (extracellular). Finally, apoptosis is a coordinated and often energy-dependent process that involves the activation of a group of cysteine proteases called “caspases” and a complex cascade of events that link the initiating stimulus to the final demise of the cell.
Many pathological conditions feature excessive cellular apoptosis (i.e., neurodegenerative diseases, AIDS, ischemia, radiation exposure, to name a few) and thus may benefit from therapeutically preventing or reducing apoptosis-induced cell death. For example, excessive cellular apoptosis is thought to play an important role in myocardial ischemia caused by an insufficient blood supply, leading to a decrease in oxygen delivery to, and subsequent death of, the cardiomyocytes. The methods of the invention may be useful to prevent or reduce the number of cardiomyocytes undergoing apoptosis-induced death.